This proposal describes a 5-year training program for the career development of the principal investigator who has completed structured residency training in Internal Medicine at the University of Texas, San Antonio, followed by fellowship training in Allergy and Immunology at Yale University. The PI plans to expand upon his prior research experience in structural biology through a comprehensive integration of interdepartmental resources at the University of Washington. The program will develop unique expertise in molecular structure-based design of specific inhibitors of signal transduction pathways. Dr. Karol Bomsztyk (Professor of Medicine and Adjunct Professor of Pharmacology), who will mentor the Pl's scientific development, is a widely recognized leader in cytokine-mediated signal transduction and has trained numerous postdoctoral fellows in cell and molecular biology. To enhance the training, co-mentors are Drs. Wim Hol and Rachel Klevit who are world leaders in structural biology using X-ray crystallography and NMR respectively. An Advisory Committee of renown scientists with expertise in computational/ combinatorial chemistry, structure-based drug design, and immunology, will provide scientific and career guidance. Research will determine the three-dimensional structure of K protein, a multi-functional signal transduction molecule, studied extensively by Dr. Bomsztyk. K protein, regulated by cytokines and growth factors, interacts with RNA, DNA, and protein targets, and its overexpression may lead to cell proliferation and malignant transformation. The specific aims are to determine: 1) The structural domains of K protein, and correlate them with functional regions; 2) The three-dimensional structure of KH, KI, and other domains of K protein using NMR; and 3) The structure of K protein using X-ray crystallography. This will be one of the first attempts to understand the structural biology of K protein. This customized, interdisciplinary program in the Department of Medicine, University of Washington, provides an ideal setting for the training of the principal investigator as an independent physician-scientist in molecular structure-based drug design.